For research use only. Not for therapeutic Use.
<p style=/line-height:25px/>NMS-P118 is a potent, orally available, and highly selective PARP-1 Inhibitor.<br>IC50 & Target: 0.04 μM (PARP-1, in HeLa cell)[1]<br><br>KD & Target: 0.009 μM(PARP-1)[1]<br><br>InVitro: NMS-P118 is found to be less myelotoxic in vitro than olaparib (now marketed as Lynparza), a dual PARP-1/-2 inhibitor. NMS-P118 proves to be metabolically stable, it modestly inhibites two cytochrome P450 family members (CYP-2B6 IC50: 8.15 μM; CYP-2D6 IC50: 9.51 μM) out of eight isoforms tested. Its ability in hampering the proliferation of bone marrow cells is from 5 to > 60 times lower then olaparib according to the species[1].<br>InVivo: NMS-P118 is a potent (KD = 0.009 μM) PARP-1 inhibitor, showing 150-fold selectivity over PARP-2 (KD = 1.39 μM). NMS-P118 possesses excellent pharmacokinetic profile and nearly complete oral bioavailability both in mice and rats. It proved to be highly efficacious in vivo both as single agent in MDA-MB-436 human breast cancer tumors and in combination with temozolomide in CAPAN-1 human pancreatic tumors growing as xenografts in the mouse. The compound is well tolerated at highly efficacious doses and is endowed with an excellent ADME profile[1].</p>
| Catalog Number | I001056 |
| CAS Number | 1262417-51-5 |
| Synonyms | 2-[1-(4,4-difluorocyclohexyl)-4-piperidinyl]-6-fluoro-2,3-dihydro-3-oxo-1H-isoindole-4-carboxamide |
| Molecular Formula | C20H24F3N3O2 |
| Purity | ≥95% |
| Target | 0.04 μM (PARP-1, in HeLa cell)[1] |
| Solubility | DMSO: ≤ 16 mg/mL |
| Storage | -20°C |
| InChI | InChI=1S/C20H24F3N3O2/c21-13-9-12-11-26(19(28)17(12)16(10-13)18(24)27)15-3-7-25(8-4-15)14-1-5-20(22,23)6-2-14/h9-10,14-15H,1-8,11H2,(H2,24,27) |
| InChIKey | ARYVAQSYRLZVQD-UHFFFAOYSA-N |
| SMILES | FC1(F)CCC(N2CCC(N(CC3=C4C(C(N)=O)=CC(F)=C3)C4=O)CC2)CC1 |
| Reference | 1:J Med Chem. 2015 Sep 10;58(17):6875-98. doi: 10.1021/acs.jmedchem.5b00680. Epub 2015 Aug 26. Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.Papeo G,Posteri H,Borghi D,Busel AA,Caprera F,Casale E,Ciomei M,Cirla A,Corti E,D/’Anello M,Fasolini M,Forte B,Galvani A,Isacchi A,Khvat A,Krasavin MY,Lupi R,Orsini P,Perego R,Pesenti E,Pezzetta D,Rainoldi S,Riccardi-Sirtori F,Scolaro A,Sola F,Zuccotto F,Felder ER,Donati D,Montagnoli A, PMID: 26222319 DOI: 10.1021/acs.jmedchem.5b00680 </br><span>Abstract:</span> The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity. |
